Methods and materials for therapeutic delivery

ABSTRACT

Method for preparing a supramolecular therapeutic agent delivery assembly are provided. A carbonate-containing precursor, a functionalized aliphatic precursor, and an aromatic diamine precursor may be combined to form an amphiphilic block co-polymer. The block co-polymer undergo a cross-linking polymerization process and a therapeutic agent may be incorporated into the resulting supramolecular assembly. The supramolecular assembly may comprise HT, PHT, HA, and/or PHA materials.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of and claims benefit to co-pendingU.S. Divisional patent application Ser. No. 15/080,272, filed Mar. 24,2016 and U.S. patent application Ser. No. 14/311,223, filed Jun. 20,2014, the entirety of which are herein incorporated by reference.

BACKGROUND

The present disclosure relates to a supramolecular assembly fortherapeutic agent delivery, and more specifically, to the use ofhexahydrotriazine (HT) and hemiaminal (HA)molecules, oligomers, andpolymers derived from aromatic, aliphatic, and/or polyether diamines tocreate carbonate containing supramolecular therapeutic agent deliveryassemblies.

Biodegradable polymers are receiving increasing attention in a widevariety of medical and pharmaceutical applications. Synthetic polymersare of particular interest as the synthetic polymers may providedesirable versatility in delivering various therapeutic agents.Synthetic polymers may be tailored, copolymerized or produced withvariations in operational conditions to tune specific properties ortarget specific needs or applications. Various properties of syntheticpolymers that may be selectively modified include hydrophobicity,crystallinity, degradability, solubility, and resistivity to specific pHconditions, among others. These synthetic polymers may be configured toprovide therapeutic agents in topical or oral delivery applications.Typical components of oral delivery applications include polymers, suchas polystyrene or polyacrylates, utilized as a non-degradable scaffoldwhich is physically blended with the therapeutic agent. The polymers arethen passed through the intestine intact after digestion. However,currently utilized polymers often lack characteristics which allow forhighly targeted therapeutic delivery. Consequently, the therapeuticagent is delivered with a reduced degree localized metabolismspecificity with little or no control over the rate at which thetherapeutic agent enters the bloodstream.

Thus, what is needed in the art are improved materials for therapeuticagent delivery.

SUMMARY

In one embodiment, a method of preparing a supramolecular therapeuticagent delivery assembly is provided. The method includes providing afirst precursor, a second precursor, and a third precursor. A ringopening polymerization may be performed to form a block co-polymer. Theblock co-polymer may be cross linked by performing a polymerizationprocess to form a supramolecular assembly and a therapeutic agent may beincorporated into the supramolecular assembly.

In another embodiment, a method of preparing a supramoleculartherapeutic agent delivery assembly is provided. The method includesproviding a carbonate-containing precursor, a functionalized aliphaticprecursor, and an aromatic diamine precursor. A ring openingpolymerization may be performed to form a block co-polymer. A PHTmaterial may be formed to cross-link the block co-polymer to form asupramolecular assembly and a therapeutic agent may be incorporated intothe supramolecular assembly.

In yet another embodiment, a method of preparing a supramoleculartherapeutic agent delivery assembly is provided. The method includesproviding a first precursor, a second precursor, and a third precursor.A ring opening polymerization may be performed to form a blockco-polymer. The block co-polymer may be cross-linked by performing apolymerization process to form a supramolecular assembly. Thesupramolecular assembly may comprise an HT material having a pluralityof trivalent hexahydrotriazine groups having the structure

anda plurality of divalent bridging groups having the structure

each divalent bridging group bonded to two of the trivalenthexahydrotriazine groups, wherein L′ is a divalent linking group. Atherapeutic agent may also be incorporated into the supramolecularassembly.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 illustrates a flow diagram summarizing a method of forming asupramolecular therapeutic agent delivery assembly according to oneembodiment.

DETAILED DESCRIPTION

Hexahydrotriazine (HT) materials and hemiaminal (HA) materials derivedfrom aromatic, aliphatic, and/or polyether diamines may be used as aplatform for creating supramolecular therapeutic agent deliveryassemblies. The supramolecular therapeutic agent delivery assembly maybe prepared from a carbonate precursor, a functionalized aliphaticprecursor, and an aromatic diamine precursor. The precursors may beutilized to prepare a block co-polymer. The supramolecular therapeuticagent delivery assembly may include single molecule species, oligomers,and/or polymers (i.e., polyhexahydrotriazine, PHT, polyhemiaminal, PHA).The supramolecular therapeutic agent delivery assembly may be made usingan aromatic diamine to react with a formaldehyde (i.e. formaldehyde orparaformaldehyde) to facilitate polymeric cross-linking of the blockco-polymer. Such supramolecular therapeutic agent delivery assemblieswill generally form a micellular structure within which a therapeuticagent may be incorporated. In certain embodiments, the supramolecularassembly may be defined in an aqueous environment. A carbonate moiety ofthe supramolecular therapeutic agent delivery assembly may be configuredto selectively deliver the therapeutic agent within a desired biologicalenvironment.

FIG. 1 is a flow diagram summarizing a method 100 of forming asupramolecular therapeutic agent delivery assembly according to oneembodiment. At operation 110 various precursors for forming thesupramolecular therapeutic agent delivery assembly are provided. In oneembodiment, the precursors may include a carbonate-containing precursors(B, C), and an aromatic diamine precursor (A). Exemplary precursors areshown below.

A hydrophobic carbonate-containing precursor is shown above andrepresented as C. The carbonate-containing precursor may be a cycliccarbonate prepared from various materials under suitable processconditions. In one embodiment, the cyclic carbonate precursor may beprepared from 6-hydroxymethyl propionic acid. Although depicted ascomprising a 6 member ring, the cyclic carbonate may include a 5-memberring or a 7-member ring. The carbonate-containing precursor may alsoinclude a carbonyl moiety. The carbonyl moiety may be bound to afunctional group (G), which may be a functional group or a radical. Thefunctional group may be selected from one or more of an amine containingmolecule, an oxygen containing molecule, or a sulfur containingmolecule, and combinations thereof, among others. The functional group(G) may be bound to the inorganic molecule and may be an arylsubstituent, an alkyl substituent, or a combination thereof. In oneembodiment, the functional group (G) may include one or morepentafluorophenyl esters. It is contemplated that any suitable cycliccarbonate that exhibits desirable hydrophobic characteristics and pHselectivity may be utilized.

The aromatic diamine precursor is shown above and represented as A. Thearomatic diamine precursor may be an amino aniline monomer prepared fromvarious materials under suitable process conditions. In one embodiment,the aromatic diamine precursor may be 4-(aminomethyl)aniline, however itis contemplated that various other aromatic diamines may be utilized.

In another embodiment, the precursors may include an aromatic diamineprecursor (A), a carbonate/PEG precursor (B), and a cyclic carbonateprecursor (C). Exemplary precursors are shown below.

At operation 120, a ring opening polymerization may be utilized toprepare a block co-polymer. In one embodiment, the ring openingpolymerization is an organocatalytic ring opening polymerization. Thecarbonate-containing precursor (C), the carbonate/PEG precursor (B), andthe aromatic diamine precursor (A) may be reacted under conditionssuitable to form the block co-polymer composed of varying stoichiometryof the precursors.

The carbonate-containing precursor, the carbonate/PEG precursor, and thearomatic diamine may be combined in a solution comprising a solvent,which may be dichloromethane (DCM), and an organic catalyst, such asdiazabicyloundecene (DBU). The reaction may proceed at room temperaturefor about 3 hours and the resulting block co-polymer may be precipitatedin methanol. The reaction conditions may facilitate formation of theblock co-polymer at the non-aniline amine due to the reducednucleophilicity of the aromatic diamine precursor. Thus, the cycliccarbonate may react with the aliphatic amine. As such, the resultingblock co-polymer may be end terminated with the aromatic diamines.

In another embodiment, the aromatic diamine precursor (A) may be reactedunder suitable conditions with the carbonate/PEG precursor (B) to formthe block co-polymer. In one embodiment, the reaction may be a ringopening polymerization, such as an organocatalytic ring openingpolymerization. An exemplary block co-polymer according to thisembodiment is shown below.

In this embodiment, the resulting block co-polymer has a hydrophobiccomponent (cyclic carbonate precursor (C)) and a hydrophilic component(carbonate/PEG precursor (B)). The aromatic diamine precursor (A) may bedisposed on a terminus of the hydrophobic component of the blockco-polymer. In this embodiment, the block co-polymer may be consideredmonofunctional. However, it is contemplated that the addition of variousfunctional groups, for example, amines or proteins, may be integratedwith the aromatic diamine precursor (A) to improve therapeutic agentdelivery selectivity and cross-linking during a subsequentpolymerization process.

In another embodiment, the aromatic diamine precursor (A) may be reactedunder suitable conditions with the cyclic carbonate precursor (C) toform the block co-polymer. In one embodiment, the reaction may be a ringopening polymerization, such as an organocatalytic ring openingpolymerization. An exemplary block co-polymer according to thisembodiment is shown below.

In this embodiment, the resulting block co-polymer has a hydrophobiccomponent (cyclic carbonate precursor (C)) and a hydrophilic component(carbonate/PEG precursor (B)). The aromatic diamine precursor (A) may bedisposed on a terminus of the hydrophilic component of the blockco-polymer. In this embodiment, the block co-polymer may be consideredmonofunctional. However, it is contemplated that the addition of variousfunctional groups, for example, amines or proteins, may be integratedwith the aromatic diamine precursor (A) to improve therapeutic agentdelivery selectivity and cross-linking during a subsequentpolymerization process.

The block co-polymer may be an amphiphilic co-polymer. In oneembodiment, the hydrophilic component (functionalized aliphaticprecursor (A) or carbonate/PEG precursor (B)) of the block co-polymerand the hydrophobic component (carbonate-containing precursor(C)) of theblock co-polymer may be present in varying amounts. For example, theratio of the hydrophilic component to the hydrophobic component may bebetween about 80:20 and about 60:40, such as about 70:30. Due to theamphiphilic nature of the block co-polymer, the block co-polymer mayself-assemble into a micelle in an aqueous environment. For example, thehydrophobic carbonate component of the block co-polymer may besurrounded by the hydrophilic functionalized aliphatic component.Polymer molecules may form a micelle structure by arranging themselvesin a spherical pattern with the hydrophobic component of each moleculepointing toward the center of the sphere and the hydrophilic componentof each molecule pointing toward the surface of the sphere.

At operation 130, a HT, polyhexahydrotriazine (PHT), HA, orpolyhemiaminal (PHA) polymerization process may be performed tocross-link the block co-polymer. The supramolecular assembly is formedspontaneously upon the addition of water and this dynamic assembly canbe stabilized by crosslinking of the periphery or the core. In oneexample, the aromatic diamine component of the block co-polymer, such as4-(aminomethyl)aniline, may be reacted with a formaldehyde (i.e.paraformaldehyde and subsequently cured to enhance covalentcross-linking of the block co-polymer via condensation reactions. In oneembodiment, the curing may be performed by heating the block co-polymerto between about 50° C. and about 280° C., such as greater than about180° C., for example, about 200° C. Examples according to variousembodiments described above are shown below.

In the embodiment shown above, the polymerization process of operation130 may result in increased cross-linking of the hydrophobic componentwhich is the core of the micellular supramolecular assembly as comparedto the hydrophilic shell component of the micellular supramolecularassembly. The localized cross-linking results from the relationshipbetween the hydrophobic component and the aromatic diamine during thepolymerization process of operation 130. Thus, tuning of the core of themicellular structure may be improved to mitigate dynamic assembly of thesupramolecular assembly.

In the embodiment shown above, the polymerization process of operation130 may result in increased cross-linking of the hydrophilic componentwhich is the shell of the micellular supramolecular assembly as comparedto the hydrophobic core component of the micellular supramolecularassembly. The localized cross-linking results from the relationshipbetween the hydrophilic component and the aromatic diamine during thepolymerization process of operation 130. Thus, tuning of the peripheryof the micellular structure may be improved to mitigate dynamic assemblyof the supramolecular assembly.

A PHT material suitable for forming an the supramolecular therapeuticagent delivery assembly as described herein is a molecule, oligomer, orpolymer that has a plurality of trivalent hexahydrotriazine groupshaving the structure

and

-   -   a plurality of divalent bridging groups of formula (2):

wherein L′ is a divalent linking group selected from the groupconsisting of *—O—*, *—S—*, *—N(R′)—*, *—N(H)—*, *—R″—*, andcombinations thereof, wherein R′ comprises at least 1 carbon and R″comprises at least one carbon, each starred bond of a givenhexahydrotriazine group is covalently linked to a respective one of thedivalent bridging groups, and each starred bond of a given bridginggroup is linked to a respective one of the hexahydrotriazine groups. Inone embodiment, R′ and R″ are independently selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, phenyl, and combinationsthereof. Other L′ groups include methylene (*−CH₂—*), isopropylidenyl(*—C(Me)₂-*), and fluorenylidenyl:

For PHT materials with bridging groups of formula (2), the HT may berepresented by formula (3):

wherein L′ is a divalent linking group selected from the groupconsisting of *—O—*, *—S—*, *—N(R′)—*, *—N(H)—*, *—R″—*, andcombinations thereof, wherein R′ and R″ independently comprise at least1 carbon. Each nitrogen having two starred wavy bonds in formula (3) isa portion of a different hexahydrotriazine group.

The PHT may also be represented by the notation of formula (4):

wherein x′ is moles, L′ is a divalent linking group selected from thegroup consisting of *—O—*, *—S—*, *—N(R′)—*, *—N(H)—*, *—R″—*, andcombinations thereof, wherein R′ comprises at least 1 carbon and R″comprises at least one carbon. Each starred bond of a givenhexahydrotriazine group of formula (4) is covalently linked to arespective one of the bridging groups. Additionally, each starred bondof a given bridging group of formula (2) is covalently linked to arespective one of the hexahydrotriazine groups. Polymer molecules may becapped or terminated by a capping group in place of a bridging group informulas (3) and (4). Examples of capping groups include CH₃, hydrogenatoms, ether groups, thioether groups, and dimethyl amino groups.

The PHT or HT can be bound non-covalently to water and/or a solvent(e.g., by hydrogen bonds).

Exemplary non-limiting divalent bridging groups include:

and combinations thereof.

A suitable PHT material may be made by forming a first mixturecomprising i) one or more monomers comprising two aromatic primary aminegroups, ii) an optional diluent monomer comprising one aromatic primaryamine group, iii) paraformaldehyde, formaldehyde, and/or anothersuitable aldehyde, and iv) a solvent, and heating the first mixture at atemperature of about 50° C. to about 300° C., preferably about 165° C.to about 200° C., thereby forming a second mixture comprising apolyhexahydrotriazine. The heating time at any of the above temperaturescan be for about 1 minute to about 24 hours. Diamine monomers suitablefor making such PHT materials may have the general structureH₂N—Ar-L′-Ar—N—H₂, where Ar denotes a benzene ring group and L′ isdefined as described above. Diluent monomers suitable for including inthe reaction are typically primary monoamines RNH₂, where the group Rbonded to nitrogen has a structure according to formula (5), formula(6), formula (7), and/or formula (8):

wherein W′ is a monovalent radical selected from the group consisting of*—N(R¹)(R²), *—OR³, —SR⁴, wherein R¹, R², R³, and R⁴ are independentmonovalent radicals comprising at least 1 carbon. The starred bonds informulas (5), (6), (7), and (8) denote bonds with the nitrogen atom ofthe primary amine monomer. Non-limiting exemplary diluent groupsinclude:

Diluent groups can be used singularly or in combination.

Non-limiting exemplary monomers comprising two primary aromatic aminegroups include 4,4′-oxydianiline (ODA), 4,4′-methylenedianiline (MDA),4,4′-(9-fluorenylidene)dianiline (FDA), p-phenylenediamine (PD),1,5-diaminonaphthalene (15DAN), 1,4-diaminonaphthalene (14DAN), andbenzidene, which have the following structures:

Non-limiting exemplary diluent monomers includeN,N-dimethyl-p-phenylenediamine (DPD), p-methoxyaniline (MOA),p-(methylthio)aniline (MTA), N,N-dimethyl-1,5-diaminonaphthalene(15DMN), N,N-dimethyl-1,4-diaminonaphthalene (14DMN), andN,N-dimethylbenzidene (DMB), which have the following structures:

HT and HA materials may be used to cross-link the block co-polymer andprovide a scaffold structure for incorporation of a therapeutic agent.It should be noted that many diamines will react with aldehydes, such asformaldehyde, to cross-link the block co-polymer. Alkyl diamines, suchas hexane diamine, will also react with formaldehyde to cross-link theblock co-polymer. The polyether and alkyl derived materials may formgels, oligomers, and small molecules that are usable as a therapeuticagent delivery assembly.

A related material that may be used to cross-link the block co-polymeris a hemiaminal (HA) material. A polyhemiaminal (PHA) is a crosslinkedpolymer comprising i) a plurality of trivalent hemiaminal groups offormula (9):

covalently linked to ii) a plurality of bridging groups of formula (10):K′

*)_(y′)  (10),wherein y′ is 2 or 3, and K′ is a divalent or trivalent radicalcomprising at least one 6-carbon aromatic ring. In formulas (9) and(10), starred bonds represent attachment points to other portions of thechemical structure. Each starred bond of a given hemiaminal group iscovalently linked to a respective one of the bridging groups.Additionally, each starred bond of a given bridging group is covalentlylinked to a respective one of the hemiaminal groups.

As an example, a polyhemiaminal can be represented by formula (11):

In this instance, each K′ is a trivalent radical (y′=3) comprising atleast one 6-carbon aromatic ring. It should be understood that eachnitrogen having two starred wavy bonds in formula (11) is a portion of adifferent hemiaminal group.

The structure of formula (11) can also be represented using the notationof formula (12):

(12), wherein x′ is moles and each bridging group K′ is a trivalentradical (y′=3 in formula (10)) comprising at least one 6-carbon aromaticring. It should be understood that each starred nitrogen bond of a givenhemiaminal group of formula (12) is covalently linked to a respectiveone of the bridging groups K′. Additionally, each starred bond of agiven bridging group K′ of formula (12) is covalently linked to arespective one of the hemiaminal groups.

Non-limiting exemplary trivalent bridging groups for HA materialsinclude:

The bridging groups can be used singularly or in combination.

Polyhemiaminals composed of divalent bridging groups K′ can berepresented herein by formula (13):

wherein K′ is a divalent radical (y′=2 in formula (10)) comprising atleast one 6-carbon aromatic ring. Each nitrogen having two starred wavybonds in formula (13) is a portion of a different hemiaminal group.

More specific divalent bridging groups have the formula (14):

wherein L′ is a divalent linking group selected from the groupconsisting of *—O—*, *—S—*, *—N(R′)—*, *—N(H)—*, *—R″—*, andcombinations thereof, wherein R′ and R″ independently comprise at least1 carbon. In an embodiment, R′ and R″ are independently selected fromthe group consisting of methyl, ethyl, propyl, isopropyl, phenyl, andcombinations thereof. Other L′ groups include methylene (*—CH₂—*),isopropylidenyl (*—C(Me)₂-*), and fluorenylidenyl:

Polyhemiaminals composed of divalent bridging groups of formula (14) canbe represented herein by formula (15):

wherein L′ is a divalent linking group selected from the groupconsisting of *—O—*, *—S—*, *—N(R′)—*, *—N(H)—*, *—R″—*, andcombinations thereof, wherein R′ and R″ independently comprise at least1 carbon. Each nitrogen having two starred wavy bonds in formula (15) isa portion of a different hemiaminal group.

The polyhemiaminal of formula (15) can also be represented by thenotation of formula (16):

wherein x′ is moles, and L′ is a divalent linking group selected fromthe group consisting of *—O—*, *—S—*, *—N(R′)—*, *—N(H)—*, *—R″—*, andcombinations thereof, wherein R′ and R″ independently comprise at least1 carbon. Each starred nitrogen bond of a given hemiaminal group offormula (16) is covalently linked to a respective one of the bridginggroups. Additionally, each starred bond of a given bridging group offormula (16) is covalently linked to a respective one of the hemiaminalgroups.

The hemiaminal groups can be bound non-covalently to water and/or asolvent. A non-limiting example is a hemiaminal group that is hydrogenbonded to two water molecules as shown in formula (17):

In some embodiments, a hemiaminal material may form a covalent networkwith water molecules that may be a polyhemiaminal hydrate (PHH). A PHAmaterial of this form may be made, for example, by reaction ofpolyethylene glycol oligomers with paraformaldehyde. Such materials maybe organogels in some cases.

Typical HT and HA polymers and oligomers, and PHH materials, asdescribed herein may be disassembled in aqueous solutions. HT oligomersand polymers will disassemble into monomers and may dissolve in acidsolutions having pH less than about 3, such as less than about 2.5, forexample less than about 2.

An HA material suitable for use according to the methods describedherein may be made using the same groups of reactants as for the HTmaterials. The diluent monomers described above may also be used to makeHA materials. A method of preparing a polyhemiaminal (PHA) comprisingdivalent bridging groups comprises forming a first mixture comprising i)a monomer comprising two or more primary aromatic amine groups, ii) anoptional diluent monomer comprising one aromatic primary amine group,iii) paraformaldehyde, and iv) a solvent. The first mixture is thenpreferably heated at a temperature of about 20° C. to about 120° C. forabout 1 minute to about 24 hours, thereby forming a second mixturecomprising the PHA. In an embodiment, the monomer comprises two primaryaromatic amine groups. The mole ratio of paraformaldehyde: total molesof primary aromatic amine groups (e.g., diamine monomer plus optionalmonoamine monomer) may be about 1:1 to about 1.25:1, based on one moleor equivalent of paraformaldehyde equal to 30 grams. The solvent can beany suitable solvent. Exemplary solvents include dipolar aproticsolvents such as, for example, N-methyl-2-pyrrolidone (NMP),dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), Propylene carbonate (PC),N-cyclohexyl-2-pyrrolidone (CHP), N,N′-dimethylpropyleneurea (DMPU), andpropylene glycol methyl ether acetate (PGMEA).

A PHT material may be prepared from a PHA material. The PHT can beprepared by heating a solution comprising the PHA at a temperature of atleast 50° C., such as about 165° C. to about 280° C. or about 180° C. toabout 220° C., for example at about 200° C. for about 1 minute to about24 hours. Additionally, a mixed PHA/PHT copolymer may be made bypartially converting a PHA material to a PHT material. A combination oflow conversion temperature, for example about 150° C. to about 165° C.,and short conversion time, for example about 1 minute to about 10minutes, may be used to make a mixed PHA/PHT material.

An exemplary PHA material may be made by reaction of 4,4′-oxydianiline(ODA) with paraformaldehyde (PF). The product is a powder or solidplastic.

4,4′-Oxydianiline (ODA, 0.20 g, 1.0 mmol) and paraformaldehyde (PF, 0.15g, 5.0 mmol, 5 equivalents (eq.)) were weighed out into a 2-Dram vialinside a N₂-filled glovebox. N-methylpyrrolidone (NMP, 6.2 g, 6.0 mL,0.17 M) was added. The vial was capped but not sealed. The reactionmixture was removed from the glovebox, and heated in an oil bath at 50°C. for 24 hours (after approximately 0.75 hours, the polymer begins toprecipitate). The polyhemiaminalP-1 was precipitated in acetone orwater, filtered and collected to yield 0.22 g, >98% yield as a whitesolid.

A second exemplary PHA material may be prepared by reaction of4,4′-methylenedianiline (MDA) with PF:

ODA was substituted with 4,4′-methylenedianiline (MDA) and a mole ratioof MDA to PF of 1:5 was used. Solid yield of 0.15 g, 69%, was anamorphous, insoluble off-white powder.

A PHT material may be prepared by reaction of ODA and PF, as follows:

P-4, a polyhexahydrotriazine, was prepared by reaction of4,4′-oxydianiline (ODA) with paraformaldehyde (PF). ODA (0.20 g, 1.0mmol) and PF (0.15 g, 5.0 mmol, 2.5 eq.) were weighed out into a 2-Dramvial inside a N₂-filled glovebox. NMP (6.2 g, 6.0 mL, 0.17 M) was added.The reaction mixture was removed from the glovebox, and heated in an oilbath at 200° C. for 3 hours (after approximately 0.25 hours, the polymerbegins to gel in the NMP). The solution was allowed to cool to roomtemperature and the polymer was precipitated in 40 mL of acetone,allowed to soak for 12 hours, then filtered and dried in a vacuum ovenovernight and collected to yield 0.21 g, 95% yield of P-4 as anoff-white solid.

The components of the supramolecular therapeutic agent delivery assemblydescribed herein may be included in a composite material that may beused for therapeutic agent delivery. Any desired polymer may form acomposite material with an HA, HT, or PHH material to provide selectedproperties. Carbon nanotubes may also form a composite with HA, HT, orPHH materials to provide additional mechanical integrity in therapeuticagent delivery applications.

At operation 140, a therapeutic agent may be incorporated into thesupramolecular assembly. The therapeutic agent may be any biologicallyactive material which can be utilized in therapeutic applications.Examples of the therapeutic agent include pharmaceuticals which arefunctionalized with nitrogen-containing groups, such as free amines. Thetherapeutic agent may be incorporated into the hydrophobic component ofthe supramolecular therapeutic agent delivery assembly covalently orotherwise physically mixed into the supramolecular therapeutic agentdelivery assembly. The therapeutic agent may be covalently associatedwith the hydrophobic component in the supramolecular therapeuticdelivery assembly. Various other interactions, such as hydrogen bonding,ionic interactions, dipole interactions, and Van der Waals interactions,between the therapeutic agent and the hydrophobic component may alsofunction to incorporate the therapeutic agent in the supramoleculartherapeutic delivery assembly.

At operation 150, the supramolecular therapeutic agent delivery assemblymay be delivered to a biological target. The biological target may be abiological system, such as a human in vivo environment. In thisembodiment, oral delivery of the supramolecular therapeutic agentdelivery assembly in a pill or capsule is envisioned. However, thesupramolecular therapeutic agent delivery assembly may also beconfigured for topical applications. In one embodiment, it may bedesirable to deliver the therapeutic agent to the intestines where moredesirable conditions for delivery of the therapeutic agent may beutilized. The PHT material of the supramolecular therapeutic agentdelivery assembly is generally resistant to acidic conditions. Forexample, the PHT material will not decompose at pH=2, which is a similarpH to the acidic environment found in the stomach.

Similarly, the hydrophobic carbonate component may also be resistant tothe acidic environment and the supramolecular therapeutic agent deliveryassembly may pass through the stomach to the intestine where the pH isnormally within the range of 7-8. The hydrophobic carbonate componentmay be susceptible to a more basic environment and may decompose in adifferent biological environment, such as the intestines. As a result ofthe decomposition of the hydrophobic carbonate component, which wasprimarily responsible for bonding or incorporating the therapeutic agentinto the supramolecular therapeutic agent delivery assembly, thetherapeutic agent may be released into the desired biologicalenvironment. The therapeutic agent may then diffuse across theendothelium of the intestines and enter the bloodstream. Upon release ofthe therapeutic, the unmetabolized hydrophilic and PHT materialcomponents of the supramolecular therapeutic agent delivery assembly maybe expelled from the biological environment.

While the foregoing is directed to example embodiments of the presentdisclosure, other and further embodiments may be devised withoutdeparting from the basic scope thereof, and the scope thereof isdetermined by the claims that follow.

What is claimed is:
 1. A method of preparing a micellar assembly,comprising: providing a first mixture of a cyclic carbonate-containingmaterial, a carbonate/PEG precursor, and a diamine material wherein thecyclic carbonate-containing material is formula (C):

wherein X is —N(H)—, —O—, or —S—, and R is aryl or alkyl, and whereinthe carbonate/PEG precursor is formula (B):

wherein n is an integer greater than 10, and wherein the diaminematerial is

performing a ring opening polymerization from the first mixture to forma block co-polymer; providing a trivalent bridging group monomer havingthe structure

or combinations thereof; providing a formaldehyde material; andperforming a polyhexahydrotriazine polymerization process on a secondmixture of the block co-polymer, the trivalent bridging group monomer,and the formaldehyde material to form a micellar assembly comprising apolyhexahydrotriazine material having a plurality of trivalenthexahydrotriazine groups having the structure

wherein each nitrogen of the trivalent bridging group is a nitrogenincorporated into one or more of the hexahydrotriazine groups afterpolymerization.
 2. The method of claim 1, further comprising providing adivalent bridging group monomer in the polyhexahydrotriazinepolymerization, the divalent bridging group monomer having the structure

wherein L′ is a divalent linking group selected from —O—, —S—, —N(R′)—,—N(H)—, —R″—, and combinations thereof wherein R′ and R″ eachindependently comprise at least one carbon and are each independentlyselected from the group consisting of methyl, ethyl, propyl, isopropyl,phenyl, and combinations thereof.
 3. The method of claim 2, furthercomprising providing a diluent group monomer in thepolyhexahydrotriazine polymerization, the diluent group monomercomprising an aromatic primary amine.
 4. The method of claim 1, furthercomprising providing a diluent group monomer in thepolyhexahydrotriazine polymerization, the diluent group monomercomprising an aromatic primary amine.
 5. The method of claim 1, whereina therapeutic agent is covalently linked to a hydrophobic component ofthe micellar assembly, the therapeutic agent comprising a free amine. 6.The method of claim 1, wherein performing the polyhexahydrotriazinepolymerization process further comprises adding to the second mixture asolvent selected from the group consisting of N-methyl-2-pyrrolidone(NMP), dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), propylene carbonate (PC),N-cyclohexyl-2-pyrrolidone (CHP), N,N′-dimethylpropyleneurea (DMPU), andpropylene glycol methyl ether acetate (PGMEA).
 7. The method of claim 6,wherein the second mixture is heated at a temperature of about 50° C. toabout 200° C. for about 1 minute to about 24 hours.
 8. A method ofpreparing a micellar assembly, comprising: providing a first mixture ofa cyclic carbonate-containing material, a carbonate/PEG precursor, and adiamine material wherein the cyclic carbonate-containing material isformula (C):

wherein X is —N(H)—, —O—, or —S—, and R is aryl or alkyl, and whereinthe carbonate/PEG precursor is formula (B):

wherein n is an integer greater than 10, and wherein the diaminematerial is

performing a ring opening polymerization from the first mixture to forma block co-polymer; providing a trivalent bridging group monomer havingthe structure

or combinations thereof; providing a formaldehyde material; performing apolyhexahydrotriazine polymerization process by reacting the blockco-polymer, the trivalent bridging group monomer, the formaldehydematerial in a second material to form a micellar assembly comprising apolyhexahydrotriazine material having a plurality of trivalenthexahydrotriazine groups having the structure

wherein each nitrogen of the trivalent bridging group is a nitrogenincorporated into one or more of the hexahydrotriazine groups afterpolymerization; and incorporating a therapeutic agent into the micellarassembly.
 9. The method of claim 8, further comprising providing adivalent bridging group monomer in the polyhexahydrotriazinepolymerization, the divalent bridging group monomer having the structure

wherein L′ is a divalent linking group selected from —O—, —S—, —N(R′)—,—N(H)—, —R″—, and combinations thereof wherein R′ and R″ eachindependently comprise at least one carbon and are each independentlyselected from the group consisting of methyl, ethyl, propyl, isopropyl,phenyl, and combinations thereof.
 10. The method of claim 9, furthercomprising providing a diluent group monomer in thepolyhexahydrotriazine polymerization, the diluent group monomercomprising an aromatic primary amine.
 11. The method of claim 8, whereina therapeutic agent is covalently linked to a hydrophobic component ofthe micellar assembly, the therapeutic agent comprising a free amine.12. The method of claim 1, further comprising physically mixing atherapeutic agent into the micellar assembly.
 13. The method of claim12, wherein the therapeutic agent comprises a free amine.
 14. A methodof preparing a micellar assembly, comprising: providing a first mixtureof a cyclic carbonate-containing material, a carbonate/PEG precursor,and a diamine material wherein the cyclic carbonate-containing materialis formula (C):

wherein X is —N(H)—, —O—, or —S—, and R is aryl or alkyl, and whereinthe carbonate/PEG precursor is formula (B):

wherein n is an integer greater than 10, and wherein the diaminematerial is

performing a ring opening polymerization from the first mixture to forma block co-polymer; providing a trivalent bridging group monomer havingthe structure

or combinations thereof; providing a diluent monomer comprising anaromatic primary amine; providing a formaldehyde material; andperforming a polyhexahydrotriazine polymerization process on a secondmixture of the block co-polymer, the trivalent bridging group monomer,the diluent group monomer, and the formaldehyde material to form amicellar assembly comprising a polyhexahydrotriazine material having aplurality of trivalent hexahydrotriazine groups having the structure

wherein each nitrogen of the trivalent bridging group is a nitrogenincorporated into one or more of the hexahydrotriazine groups afterpolymerization and a plurality of diluent group monomers; andincorporating a therapeutic agent into the micellar assembly, thetherapeutic agent comprising a free amine.
 15. The method of claim 14,wherein the diluent group monomer is selected from the group consistingof